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Trial record 3 of 16 for:    triplet | Huntington Disease

Study of BDNF Pathway Biomarkers in the Cerebrospinal Fluid in Patients With Huntington's Disease (LCR-MH)

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ClinicalTrials.gov Identifier: NCT04012411
Recruitment Status : Recruiting
First Posted : July 9, 2019
Last Update Posted : April 24, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Montpellier

Tracking Information
First Submitted Date  ICMJE July 4, 2019
First Posted Date  ICMJE July 9, 2019
Last Update Posted Date April 24, 2020
Actual Study Start Date  ICMJE March 3, 2020
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2019)
BDNF(csf) in HD subjects compared to age-matched control subjects (+/- 5 years) [ Time Frame: Inclusion ]
centralized ELISA assay with Simoa - Quanterix kit technology at the Laboratory of Clinical Proteomic Biochemistry of Montpellier, France.
Original Primary Outcome Measures  ICMJE
 (submitted: July 4, 2019)
BDNF(csf) in HD subjects compared to age-matched control subjects (+/- 5 years) [ Time Frame: Inclusion ]
the BDNF assay will be performed with SIMOA ELISA-type ultrasensitive assay with a QUanterix kit and centralized for the four centers at the Laboratory of Clinical Proteomic Biochemistry, IRMB Montpellier, France.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 11, 2019)
  • plasmatic BDNF in HD subjects vs controls [ Time Frame: Inclusion ]
  • Correlation between BDNF in CSF and BDNF in plasma [ Time Frame: Inclusion ]
  • Correlation between BDNF and disease parameters [ Time Frame: Inclusion ]
    Correlation between BDNF in CSF or plasma and: disease severity, assessed through the Huntington Disease Rating Scale (UHDRS), the disease burden formula [(n.CAG-35.5) x age], the Total Functional Capacity functional scale (TFC), and cognitive scales (Symbol Digit Modalities Test, STROOP test, Trail Making test A and B, direct and indirect digit span); - MRI brain imaging: cerebral and striatal atrophy by morphological imaging, functional resting state MRI, and anatomical connectivity by diffusion tensor imaging
  • Total Tau and NFL levels in plasma and CSF in HD subjects vs control subjects [ Time Frame: Inclusion ]
  • TrkBcsf level in subjects with HD vs control subjects [ Time Frame: Inclusion ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 4, 2019)
  • BDNF(plasma) in HD subjects vs controls [ Time Frame: Inclusion ]
  • Correlation between BDNF(csf) and BDNF(pl) [ Time Frame: Inclusion ]
  • Correlation between BDNFlcr / BDNFpl and disease parameters [ Time Frame: Inclusion ]
    Correlation between BDNFlcr / BDNFpl and: disease severity, assessed through the Huntington Disease Rating Scale (UHDRS), the disease burden formula [(n.CAG-35.5) x age], the Total Functional Capacity functional scale (TFC), and cognitive scales (Symbol Digit Modalities Test, STROOP test, Trail Making test A and B, direct and indirect digit span); - MRI brain imaging: cerebral and striatal atrophy by morphological imaging, functional resting state MRI, and anatomical connectivity by diffusion tensor imaging
  • Total Tau and NFL levels in plasma and CSF in HD subjects vs control subjects [ Time Frame: Inclusion ]
  • TrkBcsf level in subjects with HD vs control subjects [ Time Frame: Inclusion ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of BDNF Pathway Biomarkers in the Cerebrospinal Fluid in Patients With Huntington's Disease
Official Title  ICMJE Study of Brain Derived Neurotrophic Factor (BDNF) Pathway Biomarkers in the Cerebrospinal Fluid in Patients With Huntington's Disease
Brief Summary

Huntington disease (HD, 1.3/10 000) is an autosomal dominant disease due to an abnormal expansion of CAG triplets in HTT gene.

Several pathophysiological mechanisms have been evoked, including an alteration of the signaling pathway of the Brain Derived Neurotrophic Factor (BDNF), a neurotrophic factor involved in the survival of neurons (striatal and hippocampal) and synaptic plasticity. BDNF is synthesized at the level of cortical neurons and transported, through the axonal transport in which the Htt is involved, to the nerve endings; it's then secreted in response to excitatory synaptic activity, especially at the level of glutamatergic synapses. Besides, at the postsynaptic level it binds with great specificity to TrkB receptors (tropomyosin-related kinase receptors B) with a neuroprotective effect on dendritic and axonal growth and an increase in synaptic plasticity, especially at the level of the striatum and the hippocampus.

BDNF is decreased in the brain of animal models, as well as in patients with HD; the alteration of this pathway would occur in the early stages of the disease.

In the context of concomitant multiple treatments, the BNDF pathway may be one of the therapeutic targets of HD.

Moreover, in HD it remains essential to detect biological markers representative of the different pathogenic pathways that can be tested in vivo in humans to confirm the hypotheses developed at the level of basic research; these biomarkers could subsequently become biomarkers of disease progression and/or biomarkers of therapeutic efficacy of potential targeted treatments.

Therefore, this study aims to characterize potential biomarkers of the BNDF pathway in plasma and CSF in subjects with HD and to confirm the importance of this pathogenic mechanism in vivo in humans.

Detailed Description
  • Design: Multicentre prospective case-control study. Centres: University Hospital of Montpellier, France; University Hospital of Bordeaux, France; University Hospital of Nimes, France; University Hospital of Poitiers, France.
  • Main objective: To evaluate BDNF in cerebrospinal fluid as a potential marker of the BDNF-TrkB signaling pathway in vivo in HD patients at a symptomatic stage.
  • Secondary objectives: i) Evaluate plasma BDNF in subjects with HD; ii) Study the correlation between BDNF in CSF and BDNF in plasma; iii) Study the correlation between markers of the BDNF pathway and clinical severity, multimodal brain MRI parameters, and relevant markers of evolution of HD; iv) Confirm the increase of Tau and NFL (Neurofilament Light Chain) markers in plasma and in CSF, as markers of neuronal degeneration, in subjects with HD ; v) Test the TrkB assay in the CSF of patients with HD
  • Inclusion Criteria. General inclusion criteria: age ≥ 18 years old; national health insurance cover. Patient inclusion criteria: genetically confirmed Huntington's disease diagnosis (≥ 35 CAG repeat in HTT gene exon 1); written informed consent; patient agreement for LP, if requested. Control inclusion criteria: previous LP for medical reason; agreement for inclusion in a biobank for research purposes.
  • Exclusion Criteria. General exclusion criteria: subject protected by law, under curatorship or guardianship. Patients exclusion criteria: too severe HD, according to the clinician's judgment, possibly making difficult to perform cognitive evaluation or MRI; contraindications to brain MRI; contraindications to LP; inability to give informed consent. Control exclusion criteria: presence of a neurodegenerative of inflammatory central nervous system disease.
  • Inclusion period: 23 months
  • Duration of participation for each patient: 123 days maximum
  • Total research duration: 24 months
  • Plan of the study. Patients group: in 90 patients with HD, the investigators will perform: a collection of the main anamnestic and clinical data; a blood test for the determination of plasmatic BDNF, Tau and NFL and the genotyping of the Val66Met polymorphism of the BDNF gene; multimodal brain MRI with volumetry, diffusion tensor, functional MRI of rest; a measurement of the UHDRS and Total Functional Capacity scales; neuropsychological tests (SDMT, STROOP test, Trail Making Test (TMT) A and B, digit span). In a subgroup of 45 patients, the investigators will also perform a lumbar puncture for the determination of BDNF, Tau, NFL and TrkB in CSF. Control Group: 45 controls will be selected from the samples present in the existing Biobank with CSF and plasma samples available in Montpellier, France. MRI data will be centralized and processed by the Imaging Institute I2FH Montpellier University Hospital.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Huntington Disease
Intervention  ICMJE
  • Procedure: Brain MRI
    Multimodal brain MRI: volumetry, diffusion tensor, functional rest MRI
  • Procedure: Lumbar Punction
    Analysis of BDNF, Tau, NFL and TrkB in cerebrospinal fluid
  • Genetic: Blood sample
    Analysis of BDNF, Tau, NFL, and Val66Met polymorphism
  • Other: Cognitive evaluation
    Symbol Digit Modality Test (SDMT), Stroop test, Trail Making Test, Empan
Study Arms  ICMJE
  • Active Comparator: Patient with LP
    Huntington's disease patients who agreed to have LP
    Interventions:
    • Procedure: Brain MRI
    • Procedure: Lumbar Punction
    • Genetic: Blood sample
    • Other: Cognitive evaluation
  • Active Comparator: Patient without LP
    Huntington's disease patient with contraindication to LP or refusal to have LP
    Interventions:
    • Procedure: Brain MRI
    • Genetic: Blood sample
    • Other: Cognitive evaluation
  • No Intervention: Control Group
    Retrospective study with biologic samples of patients without Huntington's disease
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 4, 2019)
135
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2022
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • General inclusion criteria:

    • age ≥ 18 years-old
    • national health insurance cover
  • Patients inclusion criteria:

    • genetically confirmed Huntington's disease diagnosis (≥ 35 CAG repeat in HTT gene exon 1)
    • written informed consent
    • only for patients "with lumbar puncture (LP)": patient agreement for LP
  • Control inclusion criteria:

    • anterior LP for medical reason with consent for biobank "Neuro" with following samples present in this biobank : 2 mL blood + 0.5 mL plasma + 0.5 mL cerebrospinal fluid
    • information and non-opposition for the finality of this biobank
    • paired by age with a patient (+/- 5 years difference)

Exclusion Criteria:

  • General exclusion criteria:

    • protected by law
  • Patients exclusion criteria:

    • Huntington's disease stage too Evolved that may interfere with cognitive evaluations or MRI
    • contraindications to brain MRI
    • only for patients "with LP": contraindications to LP
    • incapacity to give informed consent
  • Control exclusion criteria:

    • neurodegenerative of inflammatory central nervous system pathology
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04012411
Other Study ID Numbers  ICMJE 19_0081
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Hospital, Montpellier
Study Sponsor  ICMJE University Hospital, Montpellier
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University Hospital, Montpellier
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP